Many useful compounds and intermediates thereof containing hydroxymethyl groups on the asymmetric carbon are known. As methods to synthesize these optically active hydroxymethylated compounds, a derivation method (Non-patent Reference 1) using readily available optically active compounds, an optical resolution method (Non-patent References 2 and 3) and a diastereoselective asymmetric synthesis reaction (Non-patent Reference 4) have previously been used. With recent progress in asymmetric synthesis methods, an increasing number of reports about catalytic asymmetric hydroxymethylation reactions have been published. However, problems such as substrate generality, yield, stereoselectivity and the like remain (Non-patent References 5-7, Patent Reference 1).
Formaldehyde, on the other hand, is the most important electrophilic agent used in organic syntheses to increase the number of carbon atoms by one, and methods in which formaldehyde is activated using a Lewis acid are frequently used in hydroxymethylation reactions. However, when a reaction is conducted in an organic solvent formaldehyde needs to be generated from a formaldehyde polymer through thermal decomposition causing serous safety and convenience problems. Formalin, that is, an aqueous solution of formaldehyde, is inexpensive and easy to handle, but formalin is difficult to activate using a Lewis acid since Lewis acids are ordinarily readily hydrolyzed.
The inventors recently discovered that rare earth metal salts are stable in aqueous solutions and function as Lewis acids, and the inventors executed hydroxymethylation reactions in aqueous solutions (Non-patent Reference 8). Furthermore, the inventors recently discovered that a chiral scandium complex was effective in a catalytic asymmetric hydroxymethylation reaction conducted using formalin in an aqueous solution (Non-patent Reference 9).
Similarly, bismuth salts exhibit highly Lewis acid type characteristics and are known to show catalytic activities better than those of scandium depending on reaction type (particularly in reactions conducted in aqueous solutions). In addition, the bismuth cation is almost non-toxic and is less expensive than scandium. However, the cyanolation reaction of aldehydes using trimethylsilyl cyanide in methylene chloride is the only catalytic asymmetric reaction known conducted using a bismuth salt (Non-patent Reference 10).    [Non-patent Reference 1]    Kaku, K. et al., Chem. Pharm. Bull., 46, 1125 (1998).    [Non-patent Reference 2]    Wu, C. et al., Tetrahedron, 57, 9575 (2001)    [Non-patent Reference 3]    Kumar, R. et al., Bioorg. Med. Chem., 9, 2643 (2001)    [Non-patent Reference 4]    Reynolds, A. et al., J. Am. Chem. Soc., 125, 12108 (2003)    [Non-patent Reference 5]    Ito, Y. et al., Chem. Commun., 1998, 71    [Non-patent Reference 6]    Yamamoto, H. et al., Synlett, 2003, 2219    [Non-patent Reference 7]    Cordova, A. et al., Tetrahedron Lett., 45, 6117 (2004)    [Patent Reference 1]    Japanese laid-open application publication (Kokai) No. 2002-200428    [Non-patent Reference 8]    Kobayashi, S. et al., Chem. Lett., 1991, 2187    [Non-patent Reference 9]    Ishikawa, S. et al., J. Am. Chem. Soc., 126, 12236 (2004)    [Non-patent Reference 10]    Wada, M. et al., Tetrahedron: Asymmetry, 8, 3939 (1997)